U.S. patent number 6,890,517 [Application Number 10/395,777] was granted by the patent office on 2005-05-10 for inhalable formulation of a solution containing a tiotropium salt.
This patent grant is currently assigned to Boehringer Ingelheim Pharma KG. Invention is credited to Petra Barth, Karin Drechsel, Barbara Niklaus-Humke, Christel Schmelzer.
United States Patent |
6,890,517 |
Drechsel , et al. |
May 10, 2005 |
**Please see images for:
( Certificate of Correction ) ** |
Inhalable formulation of a solution containing a tiotropium
salt
Abstract
A liquid, propellant-free pharmaceutical preparation comprising:
(a) a first active substance comprising a tiotropium salt, in a
concentration based on tiotropium of between 0.0005% and 5% by
weight; (b) a second active substance selected from the group
consisting of: an antiallergic, antihistamine, steroid, and
leukotriene antagonist; (c) a solvent selected from water or a
water/ethanol mixture; and (d) a pharmacologically acceptable
preservative, wherein the pH of the preparation is adjusted to
between 2.0 and 4.5 with an acid and the tiotropium salt is
dissolved in the solvent, optionally including a pharmacologically
acceptable complexing agent, stabilizer, a pharmacologically
acceptable cosolvent, or other pharmacologically acceptable
adjuvants and additives; a method for administering a
pharmaceutical preparation by nebulizing the pharmaceutical
preparation in an inhaler, and a method of treating asthma or COPD
in a patient using the pharmaceutical preparation.
Inventors: |
Drechsel; Karin (Mannheim,
DE), Niklaus-Humke; Barbara (Damscheid,
DE), Schmelzer; Christel (Ingelheim, DE),
Barth; Petra (Mainz, DE) |
Assignee: |
Boehringer Ingelheim Pharma KG
(Ingelheim, DE)
|
Family
ID: |
27214136 |
Appl.
No.: |
10/395,777 |
Filed: |
March 24, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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040196 |
Oct 25, 2001 |
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Foreign Application Priority Data
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Oct 31, 2000 [DE] |
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100 54 042 |
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Current U.S.
Class: |
424/45;
128/200.14; 239/333; 424/400; 514/171; 514/217.05; 514/291;
514/826 |
Current CPC
Class: |
A61K
9/0078 (20130101); A61K 31/46 (20130101); A61K
31/4745 (20130101); A61K 31/496 (20130101); A61K
31/55 (20130101); A61K 31/56 (20130101); A61K
31/57 (20130101); A61K 31/58 (20130101); A61K
45/06 (20130101); A61K 31/46 (20130101); A61K
31/4745 (20130101); A61K 31/56 (20130101); A61K
31/57 (20130101); A61K 31/58 (20130101); A61K
31/439 (20130101); A61K 31/439 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101); A61K
2300/00 (20130101); Y10S 514/826 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
31/58 (20060101); A61K 45/00 (20060101); A61K
45/06 (20060101); A61K 31/46 (20060101); A61K
31/4738 (20060101); A61K 31/55 (20060101); A61K
31/57 (20060101); A61K 31/496 (20060101); A61K
31/4745 (20060101); A61K 31/56 (20060101); A61K
009/14 (); A61K 038/00 () |
Field of
Search: |
;424/45,46,400
;514/826,217.05,291,171 ;239/333 ;128/200.14 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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42 03 306 |
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Aug 1993 |
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DE |
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19921693 |
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Jul 1997 |
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DE |
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19825027 |
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Jun 1998 |
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DE |
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19653969 |
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Nov 2000 |
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DE |
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0504112 |
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Sep 1992 |
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EP |
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WO 97/46243 |
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Dec 1997 |
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WO |
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WO 98/27959 |
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Jul 1998 |
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WO |
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WO 00/07567 |
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Feb 2000 |
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WO |
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WO 00/23037 |
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Apr 2000 |
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WO |
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WO00/47200 |
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Aug 2000 |
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WO |
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Other References
Mon, F. et al; Aerosol Therapy In Asthma, Revue Des Maladies
Respiratoires, vol. 6., No. 3, 1989, pp. 189-200. .
Balzano, G. et al; Effectiveness and Acceptability of a domicillary
multidrug inhalation treatment in elderly patients with chronic
airflow obstruction; Journal of Aerosol Medicine, The Official
Journal of the Int'l. Society for Aerosol in Medicine U.S. 2000
Spring, vol. 13, No. 1 Apr. 2000 (pp. 25-33). .
Rutgers S.R. et al; Short Term Treatment with Budesonide does not
improve hyperresponsiveness to adenosine 5'monophosphate in COPD,
American Journal of Respiratory and Critical Care Medicine, U.S.,
Mar. 1998, vol. 157, No. 3 Pt. 1,Mar. 1998 pp. 880-886. .
Van Schayck, C.P., et al; Periodic treatment regimens with inhaled
steroids in asthma or chronic obstructive pulmonary disease. Is it
possible? Journal of American Medical Association. U.S. Jul. 12,
1995, vol. 278, No. 2, Jul. 12, 1995 (1995-07) pp. 151-164. .
Naclerio, R.M.; Optimizing treatment options., Clinical and
Experimental Allergy, vol. 28., No. Suppl. 6, Dec. 1998 pp. 54-59.
.
Nishimura, K. et al.; Additive effect of Oxitroplum bromide in
combination with inhaled corticosteroids in the treatment of
elderly patients with chronic asthma. Allergology Int'l. vol. 48,
No. 1, Mar. 1999. .
Pavia, D. et al; Preliminary data from phase II studies with
Resplmat, a propellant-free soft mist inhaler, Journal of Aerosol
Medicine, The Offical Journal of the Int'l. Society for Aerosols in
Medicine U.S. 1999, vol. 12 Suppl 1, 1999, pp. S33-S39. .
Patent Abstract of Japan, vol. 1999, No. 2, Feb. 26, 1999 & JP
10 298107A (Taisho Pharmaceutical Co. Ltd) Nov. 10, 1998 Abstract.
.
English Abstract for DE 42 03 306 A1..
|
Primary Examiner: Kunz; Gary
Assistant Examiner: Haghighatian; Mina
Attorney, Agent or Firm: Morris; Michael P. Devlin;
Mary-Ellen M. Small; Andrea D.
Parent Case Text
RELATED APPLICATIONS
This is a continuation of U.S. Ser. No. 10/040,196, filed Oct. 25,
2001, now abandoned, which claimed benefit under 35 U.S.C. .sctn.
119(e) of prior provisional application Serial No. 60/253,613,
filed Nov. 28, 2000.
Claims
We claim:
1. A liquid, propellant-free pharmaceutical preparation comprising:
(a) a first active substance comprising a tiotropium salt, in a
concentration based on tiotropium of between 0.0005% and 5% by
weight; (b) a second active substance selected from the group
consisting of: an antiallergic, antihistamine, steroid, and
leukotriene antagonist; (c) a solvent selected from water or a
water/ethanol mixture; and (d) a pharmacologically acceptable
preservative, wherein the pH of the preparation is adjusted to
between 2.0 and 4.5 with an acid and the tiotropium salt is
dissolved in the solvent, optionally including a pharmacologically
acceptable complexing agent, stabilizer, a pharmacologically
acceptable cosolvent, or other pharmacologically acceptable
adjuvants and additives.
2. The pharmaceutical preparation according to claim 1, wherein the
tiotropium salt is a salt formed with HBr, HCl, HI,
monomethylsulfuric acid ester, methanesulfonic acid,
or-p-toluenesulfonic acid.
3. The pharmaceutical preparation according to claim 1, wherein the
active substance is tiotropium bromide.
4. The pharmaceutical preparation according to claim 1, wherein the
active substance is tiotropium bromide monohydrate.
5. The pharmaceutical preparation according to claim 1, wherein the
solvent is water.
6. The pharmaceutical preparation according to claim 2, wherein the
solvent is water.
7. The pharmaceutical preparation according to claim 3, wherein the
solvent is water.
8. The pharmaceutical preparation according to claim 4, wherein the
solvent is water.
9. The pharmaceutical preparation according to claim 1, wherein the
solvent is a water-ethanol mixture with up to 90 vol. % of
ethanol.
10. The pharmaceutical preparation according to claim 2, wherein
the solvent is a water-ethanol mixture with up to 90 vol. % of
ethanol.
11. The pharmaceutical preparation according to claim 3, wherein
the solvent is a water-ethanol mixture with up to 90 vol. % of
ethanol.
12. The pharmaceutical preparation according to claim 4, wherein
the solvent is a water-ethanol mixture with up to 90 vol. % of
ethanol.
13. The pharmaceutical preparation according to claim 9, wherein
the solvent is a water-ethanol mixture with up to 70 vol. % of
ethanol.
14. The pharmaceutical preparation according to claim 13, wherein
the solvent is a water-ethanol mixture with up to 30 vol. % of
ethanol.
15. The pharmaceutical preparation according to one of claims 1 to
4, wherein the pharmaceutical preparation does not contain a
complexing agent.
16. The pharmaceutical preparation according to one of claims 1 to
4, wherein the pharmaceutical preparation does not contain a
stabilizer.
17. The pharmaceutical preparation according to one of claims 1 to
4, wherein edetic acid salt is present in an amount of greater than
0 up to 25 mg/100 ml.
18. The pharmaceutical preparation according to claim 17, wherein
edetic acid salt is present in an amount of from 5 to less than 10
mg/100 ml.
19. The pharmaceutical preparation according to claim 17, wherein
the edetic acid salt is sodium edetate.
20. The pharmaceutical preparation according to one of claims 1 to
4, wherein the pH is between 2.5 and 3.5.
21. The pharmaceutical preparation according to claim 20, wherein
the pH is between 2.7 and 3.3.
22. The pharmaceutical preparation according to claim 21, wherein
the pH is between 2.7 and 3.0.
23. The pharmaceutical preparation according to one of claims 1 to
4, wherein the concentration based on tiotropium is between 0.0005%
and 5% by weight.
24. The pharmaceutical preparation according to claim 23, wherein
the concentration based on tiotropium is between 0.001% to 3% by
weight.
25. The pharmaceutical preparation according to one of claims 1 to
4, wherein the pharmacologically acceptable preservative is
benzalkonium chloride.
26. The pharmaceutical preparation according to one of claims 1 to
4, wherein the pharmaceutical preparation comprises a
pharmacologically acceptable adjuvant or additive.
27. The pharmaceutical preparation according to claim 26, wherein
pharmacologically acceptable adjuvant or additive is an
antioxidant.
28. The pharmaceutical preparation according to one of claims 1 to
4, wherein the pharmaceutical preparation contains no cosolvents
and/or pharmacologically acceptable adjuvants and additives apart
from the preservative.
29. The pharmaceutical preparation according to one of claims 1 to
4, wherein the tiotropium salt is present in a concentration based
on tiotropium of between 0.001% and 3% by weight.
30. The pharmaceutical preparation according to one of claims 1 to
4, wherein the tiotropium salt is present in a concentration based
on tiotropium of between 0.001 % and 0.1 % by weight.
31. The pharmaceutical preparation according to one of claims 1 to
4, wherein the ingredients are dissolved in the solvent.
32. The pharmaceutical preparation according to one of claims 1 to
4, wherein the second active substance is in suspension in the
solvent.
33. The pharmaceutical preparation according to one of claims 1 to
4, wherein the second active substance is a steroid.
34. The pharmaceutical preparation according to claim 33, wherein
the concentration of the steroid is 0.05 wt. % to 5 wt. %.
35. The pharmaceutical preparation according to claim 33, wherein
the steroid is selected from the group consisting of: budesonide,
beclomethasone dipropionate, fluticasone, and flunisolide.
36. The pharmaceutical preparation according to one of claims 1 to
4, wherein the second active substance is an antiallergic or an
antihistamine.
37. The pharmaceutical preparation according to claim 36, wherein
the concentration of the antiallergic or the antihistamine is 0.05
wt. % to 15 wt. %.
38. The pharmaceutical preparation according to claim 36, wherein
the antiallergic or the antihistamine is selected from the group
consisting of: epinastine, nedocromil, disodium cromoglycate,
astemizole, mequitazine, carbinoxamine, and clemastine, or a
corresponding pharmaceutically acceptable salt thereof.
39. The pharmaceutical preparation according to one of claims 1 to
4, wherein the second active substance is a leukotriene
antagonist.
40. The pharmaceutical preparation according to claim 39, wherein
the concentration of the leukotriene antagonist is 0.05 wt. % to 10
wt. %.
41. The pharmaceutical preparation according to claim 39, wherein
the leukotriene antagonist is selected from the group consisting
of: montelukast, pranlukast, zafirlukast,
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2
-propyl)phenyl)thio)methylcyclopropane-acetic acid, and
1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl
)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acet
ic acid,
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic
acid.
42. A pharmaceutical preparation according to claim 1, wherein the
pharmaceutical preparation comprises: water as the solvent; a
surfactant; 0.1 wt. % of tiotropium bromide; a second active
substance selected from the group consisting of: antiallergics,
antihistamines, steroids, and leukotriene antagonists; 0.01 wt. %
of benzalkonium chloride; and 0.05 wt. % of sodium edetate, wherein
the pH of the preparation is adjusted to 3.0 with hydrochloric acid
or citric acid.
43. A method for administering a pharmaceutical preparation
according to one of claims 1 to 4, comprising nebulizing the
pharmaceutical preparation in an inhaler selected from the group
consisting of an inhaler according to FIGS. Ia or Ib.
44. A method for administering a pharmaceutical preparation
according to one of claims 1 to 4, comprising nebulizing the
pharmaceutical preparation in an inhaler which nebulizes defined
amounts of the pharmaceutical preparation by the application of
pressures from 100 to 600 bar through a nozzle having at least one
nozzle opening with a depth of 2 to 10 microns and a width of 5 to
15 microns to form an inhalable aerosol.
45. The method according to claim 44, wherein at least one nozzle
opening is at least two nozzle openings which are inclined relative
to one another in the direction of the nozzle opening at an angle
of from 20 degrees to 160 degrees.
46. The method according to claim 44, wherein the defined amounts
of the pharmaceutical preparation are 10 to 50 microliters.
47. The method according to claim 43, wherein the inhaler is 9 cm
to 15 cm long and 2 cm to 4 cm wide.
48. The method according to claim 44, wherein the inhaler is 9 cm
to 15 cm long and 2 cm to 4 cm wide.
49. The method according to claim 43, wherein the mass of
pharmaceutical formulation delivered in at least 97% of all
actuations of the inhaler is between 5 mg and 30 mg within a range
of tolerance of 25%.
50. The method according to claim 44, wherein the mass of
pharmaceutical formulation delivered in at least 97% of all
actuations of the inhaler is between 5 mg and 30 mg within a range
of tolerance of 25%.
51. The method according to claim 43, wherein the mass of
pharmaceutical formulation delivered in at least 97% of all
actuations of the inhaler is between 5 mg and 30 mg within a range
of tolerance of 20%.
52. The method according to claim 44, wherein the mass of
pharmaceutical formulation delivered in at least 97% of all
actuations of the inhaler is between 5 mg and 30 mg within a range
of tolerance of 20%.
53. The method according to claim 43, wherein the mass of
pharmaceutical formulation delivered in at least 98% of all
actuations of the inhaler is between 5 mg and 30 mg within a range
of tolerance of 20%.
54. The method according to claim 44, wherein the mass of
pharmaceutical formulation delivered in at least 98% of all
actuations of the inhaler is between 5 mg and 30 mg within a range
of tolerance of 20%.
55. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation according to one of claims 1 to 4.
56. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 43.
57. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 44.
58. A method for administering a pharmaceutical preparation
according to claim 26, comprising nebulizing the pharmaceutical
preparation in an inhaler selected from the group consisting of an
inhaler according to FIGS. Ia or Ib.
59. A method for administering a pharmaceutical preparation
according to claim 26, comprising nebulizing the pharmaceutical
preparation in an inhaler which nebulizes defined amounts of the
pharmaceutical preparation by the application of pressures from 100
to 600 bar through a nozzle having at least one nozzle opening with
a depth of 2 to 10 microns and a width of 5 to 15 microns to form
an inhalable aerosol.
60. A method for administering a pharmaceutical preparation
according to claim 28, comprising nebulizing the pharmaceutical
preparation in an inhaler selected from the group consisting of an
inhaler according to FIGS. Ia or Ib.
61. A method for administering a pharmaceutical preparation
according to claim 28, comprising nebulizing the pharmaceutical
preparation in an inhaler which nebulizes defined amounts of the
pharmaceutical preparation by the application of pressures from 100
to 600 bar through a nozzle having at least one nozzle opening with
a depth of 2 to 10 microns and a width of 5 to 15 microns to form
an inhalable aerosol.
62. A method for administering a pharmaceutical preparation
according to claim 33, comprising nebulizing the pharmaceutical
preparation in an inhaler selected from the group consisting of an
inhaler according to FIGS. Ia or Ib.
63. A method for administering a pharmaceutical preparation
according to claim 33, comprising nebulizing the pharmaceutical
preparation in an inhaler which nebulizes defined amounts of the
pharmaceutical preparation by the application of pressures from 100
to 600 bar through a nozzle having at least one nozzle opening with
a depth of 2 to 10 microns and a width of 5 to 15 microns to form
an inhalable aerosol.
64. A method for administering a pharmaceutical preparation
according to claim 36, comprising nebulizing the pharmaceutical
preparation in an inhaler selected from the group consisting of an
inhaler according to FIGS. Ia or Ib.
65. A method for administering a pharmaceutical preparation
according to claim 36, comprising nebulizing the pharmaceutical
preparation in an inhaler which nebulizes defined amounts of the
pharmaceutical preparation by the application of pressures from 100
to 600 bar through a nozzle having at least one nozzle opening with
a depth of 2 to 10 microns and a width of 5 to 15 microns to form
an inhalable aerosol.
66. A method for administering a pharmaceutical preparation
according to claim 39, comprising nebulizing the pharmaceutical
preparation in an inhaler selected from the group consisting of an
inhaler according to FIGS. Ia or Ib.
67. A method for administering a pharmaceutical preparation
according to claim 39, comprising nebulizing the pharmaceutical
preparation in an inhaler which nebulizes defined amounts of the
pharmaceutical preparation by the application of pressures from 100
to 600 bar through a nozzle having at least one nozzle opening with
a depth of 2 to 10 microns and a width of 5 to 15 microns to form
an inhalable aerosol.
68. A method for administering a pharmaceutical preparation
according to claim 41, comprising nebulizing the pharmaceutical
preparation in an inhaler selected from the group consisting of an
inhaler according to FIGS. Ia or Ib.
69. A method for administering a pharmaceutical preparation
according to claim 41, comprising nebulizing the pharmaceutical
preparation in an inhaler which nebulizes defined amounts of the
pharmaceutical preparation by the application of pressures from 100
to 600 bar through a nozzle having at least one nozzle opening with
a depth of 2 to 10 microns and a width of 5 to 15 microns to form
an inhalable aerosol.
70. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 58.
71. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 59.
72. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 60.
73. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 61.
74. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 62.
75. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 63.
76. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 64.
77. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 65.
78. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 66.
79. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 67.
80. A method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 68.
81. method of treating asthma or COPD in a patient, the method
comprising administering to the patient a pharmaceutical
preparation using the method of claim 69.
Description
BACKGROUND OF THE INVENTION
The present invention relates to a propellant-free inhalable
formulation of a pharmaceutically acceptable salt of tiotropium
dissolved in water or a mixture of water and ethanol, in
conjunction with at least one other active substance preferably
administered by inhalation, and propellant-free inhalable aerosols
resulting therefrom. The formulation according to the invention is
particularly suitable for administering the active substance by
inhalation, especially for treating asthma and chronic obstructive
pulmonary disease (COPD).
Tiotropium, chemically (1.alpha., 2.beta., 4.beta.,
5.alpha.,7.beta.)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-
azoniatricyclo[3.3.1.0.sup.2,4 ]nonane, is known as tiotropium
bromide from European Patent Application EP 418 716 A1. The bromide
salt of tiotropium has the following chemical structure:
##STR1##
The compound has valuable pharmacological properties and is known
by the name tiotropium bromide. Tiotropium and its salts are highly
effective anticholinergics and can provide therapeutic benefit in
the treatment of asthma or COPD (chronic obstructive pulmonary
disease). The monohydrate of tiotropium bromide is also
pharmacologically valuable. Both compounds are a preferred object
of the present invention.
SUMMARY OF THE INVENTION
The present invention relates to liquid active substance
formulations of these compounds which can be administered by
inhalation; the liquid formulations according to the invention have
to meet high quality standards.
DESCRIPTION OF THE DRAWINGS
FIG. 1a shows a longitudinal section of the RESPIMAT.RTM. nebulizer
disclosed in WO 97/12687 through the atomizer with the spring under
tension; and
FIG. 1b shows a longitudinal section of the RESPIMAT.RTM. nebulizer
disclosed in WO 97/12687 through the atomizer with the spring
released.
FIGS. 1a and 1b herein are identical to FIGS. 6a and 6b of WO
97/12687.
DETAILED DESCRIPTION OF THE INVENTION
To achieve an optimum distribution of active substances in the
lung, it makes sense to use a liquid formulation without propellant
gases administered using suitable inhalers. Those inhalers which
are capable of nebulizing a small amount of a liquid formulation in
the dosage needed for therapeutic purposes within a few seconds
into an aerosol suitable for therapeutic inhalation are
particularly suitable. Within the scope of the invention, preferred
nebulizers are those in which an amount of less than 100
microliters, preferably less than 50 microliters, most preferably
less than 20 microliters of active substance solution can be
nebulized preferably in one puff to form an aerosol having an
average particle size of less than 20 microns, preferably less than
10 microns, so that the inhalable part of the aerosol already
corresponds to the therapeutically effective quantity.
An apparatus of this kind for the propellant-free administration of
a metered amount of a liquid pharmaceutical composition for
inhalation is described in detail, for example, in
International Patent Application WO 91/14468 "Atomizing Device and
Methods" and also in WO 97/12687, cf FIGS. 6a and 6b and the
accompanying description. In a nebulizer of this kind a
pharmaceutical solution is converted by means of a high pressure of
up to 500 bar into an aerosol destined for the lungs, which is
sprayed. Within the scope of the present specification reference is
expressly made to the entire contents of the literature mentioned
above.
In inhalers of this kind, the formulations of solutions are stored
in a reservoir. It is essential that the active substance
formulations used are sufficiently stable when stored and at the
same time are such that they can be administered directly, if
possible without any further handling, in accordance with their
medical purpose. Moreover, they must not contain any ingredients
which might interact with the inhaler in such a way as to damage
the inhaler or the pharmaceutical quality of the solution or of the
aerosol produced.
To nebulize the solution, a special nozzle is used as described,
for example, in WO 94/07607 or WO 99/16530, reference is expressly
made here to both these publications and each of which is
incorporated herein by reference in their entireties.
WO 98/27959 discloses formulations of solutions for the inhaler
described above which contain as additive the disodium salt of
edetic acid (sodium edetate). For aqueous formulations of solutions
which are to be converted into inhalable aerosols using the inhaler
described above, the specification favors a minimum concentration
of sodium edetate of 50 mg/100 ml, in order to reduce the incidence
of spray anomalies. Among the Examples disclosed there is a
formulation containing tiotropium bromide. In this formulation, the
active substance is dissolved in water. The proportion of sodium
edetate is again 50 mg/100 ml.
Surprisingly, it has now been found that formulations of solutions
of tiotropium salts in water or a water-ethanol mixture wherein the
proportion of the additive sodium edetate is significantly less
than 50 mg/100 ml show a reduction in the scattering of the
composition delivered, compared with the formulation containing
tiotropium bromide known from the prior art. In addition, the spray
quality is very good. The resulting aerosol has very good
properties for administration by inhalation.
Another advantage of the formulation is that, thanks to the absence
of or reduction in the additive sodium edetate in the active
substance formulation, the pH of the solution formulation can be
lowered. Low pH levels are necessary for the long-term stability of
the tiotropium salts in the formulation.
It is therefore an aim of the present invention to provide an
aqueous active substance formulation containing a pharmaceutically
acceptable tiotropium salt which meets the high standards needed in
order to be able to achieve optimum nebulization of a solution
using the inhalers mentioned hereinbefore. The active substance
formulations according to the invention must be of sufficiently
high pharmaceutical quality, i.e., they should be pharmaceutically
stable over a storage time of some years, preferably at least one
year, more preferably two years.
Another aim is to provide propellant-free formulations of solutions
containing tiotropium salts which are nebulized under pressure
using an inhaler, the composition delivered by the aerosol produced
falling reproducibly within a specified range.
Another aim is to provide formulations of solutions with tiotropium
and another active substance which can be administered by
inhalation.
According to the invention, any pharmaceutically acceptable salts
of tiotropium may be used for the formulation. When the term
tiotropium salt is used within the scope of the present invention,
this is to be taken as a reference to tiotropium. According to the
invention a reference to tiotropium, which is the free ammonium
cation, corresponds to a reference to tiotropium in the form of a
salt (tiotropium salt) which contains an anion as counter-ion.
Tiotropium salts which may be used within the scope of the present
invention are preferably compounds which contain, in addition to
tiotropium as counter-ion (anion), chloride, bromide, iodide,
methanesulfonate, p-toluenesulfonate, and/or methylsulfate.
Within the scope of the present invention tiotropium bromide is
preferred as the salt. References to tiotropium bromide within the
scope of the present invention must always be taken as references
to all possible amorphous and crystalline modifications of
tiotropium bromide. These may for example contain molecules of
solvent in their crystalline structure. Of all the crystalline
modifications of tiotropium bromide those which also contain water
(hydrates) are preferred according to the invention. It is
particularly preferred within the scope of the present invention to
use tiotropium bromide monohydrate.
In the formulations according to the invention combinations with a
tiotropium salt and only one other active substance are
preferred.
In the formulations according to the invention, the tiotropium
salts are dissolved in a solvent. The solvent may be exclusively
water, or it may be a mixture of water and ethanol. Ethanol may be
added to the formulation in order to increase the solubility of
additives or other active substances apart from the tiotropium
salt, preferably tiotropium bromide or tiotropium bromide
monohydrate. The relative proportion of ethanol to water is not
limited; it may be 90% by volume, for example. Preferably, the
maximum limit of ethanol is 70% by volume, particularly 60% by
volume and most preferably 30% by volume. The remaining % by volume
consist of water. The preferred solvent is water without the
addition of ethanol.
The concentration of the tiotropium salt based on the proportion of
tiotropium in the finished pharmaceutical preparation depends on
the therapeutic effect sought. For most of the complaints which
respond to tiotropium the concentration of tiotropium is between
0.0005% and 5% by weight, preferably between 0.001% and 3% by
weight.
The pH of the formulation according to the invention is between 2.0
and 4.5, preferably between 2.5 and 3.5 and more preferably between
2.7 and 3.5 and particularly preferably between 2.7 and 3.2. Most
preferred are pHs with an upper limit of 3.1.
The pH is adjusted by the addition of pharmacologically acceptable
acids.
Examples of inorganic acids which are preferred for this purpose
include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric
acid, and/or phosphoric acid.
Examples of particularly suitable organic acids are: ascorbic acid,
citric acid, malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid, and/or propionic acid, etc.
Preferred inorganic acids are hydrochloric acid and sulfuric acid.
It is also possible to use acids which form an acid addition salt
with the active substance or, in the case of combined preparations,
with one of the active substances.
Of the organic acids, ascorbic acid, fumaric acid and citric acid
are preferred, especially citric acid. If desired, mixtures of the
abovementioned acids may also be used, particularly in the case of
acids which have other properties in addition to their acidifying
properties, e.g., those which act as flavorings or antioxidants,
such as for example citric acid or ascorbic acid. Hydrochloric acid
deserves special mention as a preferred inorganic acid.
If desired, pharmacologically acceptable bases may be used to
titrate the pH precisely. Suitable bases include for example alkali
metal hydroxides and alkali metal carbonates. The preferred alkali
ion is sodium. If bases of this kind are used, care must be taken
to ensure that the resulting salts, which are then contained in the
finished pharmaceutical formulation, are pharmacologically
compatible with the abovementioned acid.
According to the invention, there is no need to add edetic acid
(EDTA) or one of the known salts thereof, sodium edetate, to the
present formulation as a stabilizer or complexing agent.
Another preferred embodiment contains edetic acid and/or the salts
thereof.
In a preferred embodiment with sodium edetate the content based on
sodium edetate is less than 10 mg/100 ml. In this case, there is
one preferred range from 5 mg/100 ml to less than 10 mg/100 ml or
another from greater than 0 to 5 mg/100 ml.
In another embodiment the content of sodium edetate is 10 to 30
mg/100 ml, preferably not more than 25 mg/100 ml.
In a preferred embodiment this additive is omitted entirely.
The remarks made concerning sodium edetate also apply analogously
to other comparable additives which have complexing properties and
can be used instead, such as for example nitrilotriacetic acid and
the salts thereof.
By complexing agents is preferably meant within the scope of the
present invention molecules which are capable of entering into
complex bonds. Preferably, these compounds should have the effect
of complexing cations, most preferably metal cations.
The other active substances apart from the tiotropium salt in the
combined preparation are selected in particular from among the
antihistamines, antiallergic agents, leukotriene antagonists and/or
steroids.
These active substances include:
As steroids: alclometasone, alclometasone dipropionate, alisactide,
amcinonide, aminoglutethimide, aristocort diacetate,
beclomethasone, beclomethasone-17,21-dipropionate, betamethasone
valerate, betamethasone adamantoate, budesonide, butixocort,
canesten-HC, ciclometasone, clobetasol, clobetasone, cloprednol,
cloprednol, fluocortin butyl, cortivazol, deflazacort, deflazacort,
demetex, deprodone, deprodone propionate, dexamethasone,
dexamethasone-21-isonicotinate, dexaniethasone isonicotinate,
diflorasone, difluprednate, endrisone, fluazacort, fluclorolone
acetonide, flunisolide, fluocinolone acetonide, fluocinonide,
fluocortin, fluocortolone caproate, fluodexan, fluorometholone,
fluticasone, fluticasone propionate, formebolone, formnocortal,
halcinonide, halometasone, halopredone acetate, hydrocortisone,
hydrocortisone-17-butyrate, hydrocortisone aceponate,
hydrocortisone butyrate propionate, icomethasone enbutate,
lotrisone, mazipredone, medrysone, meprednisone, methylprednisolone
aceponate, mometasone, mometasone furoate, mycophenolate mofetil,
pranlukast, paramethasone acetate, prednicarbate, promedrol,
seratrodast, tipredan, tixocortol pivalate, triamcinolone,
triamcinolone hexacetonide, trilostane, triamcinolone benetonide,
ulobetasol propionate, zileuton, and methyl
9-.alpha.-chloro-6-.alpha.-fluoro-11-.beta.-17-.alpha.-dihydroxy-16-.alpha
.-methyl-3-oxo-1,4-androstadiene-17-.beta.-carboxylate-17-propionate.
Particularly preferred are the combinations of tiotropium bromide,
or tiotropium bromide-monohydrate and budesonide, flunisolide,
beclomethasone dipropionate or fluticasone, as well as the
pharmacologically acceptable (possibly other) salts thereof.
The preferred combination comprises tiotropium bromide, or
tiotropium bromide monohydrate and budesonide.
If the combined formulation contains a leukotriene antagonist, this
is preferably selected from among montelukast, pranlukast,
zafirlukast,
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2
-propyl)phenyl)thio)methylcyclopropane acetic acid,
1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl
)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane
acetic acid or
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic
acid. Montelukast, pranlukast and/or zafirlukast are preferred.
The concentration of the leukotriene antagonist is from 0.05 wt. %
to 10 wt. %, preferably up to 5 wt. %, more preferably 0.1 wt. % to
3.5 wt. %.
The following are mentioned as examples of antihistamines and
antiallergic agents: azelastine, astemizole, bamipine,
carbinoxamine hydrogen maleate, cetirizine, dexchlorpheniramine,
chlorphenoxamine, clemastine, clemastine hydrogen fumarate,
desloratadine, dimenhydrinate, dimethindene, disodium cromoglycate,
diphenhydramine, doxylamine, ebastine, emedastine, epinastine,
fexofenadine, ketotifen, levocabastine, loratadine, meclozine,
mequitazine, mizolastine, nedocromil, pheniramine, and
promethazine. Epinastine, nedocromil, disodium cromoglycate,
astemizole, mequitazine, carbinoxamine, and clemastine, and the
corresponding pharmaceutically acceptable salts are preferred.
In the combined preparation, the concentration of the antiallergic
agents and/or antihistamines is preferably 0.05 wt. % to 15 wt. %,
preferably up to 10 wt. %, more preferably 0.1 wt. % to 10 wt. %,
most preferably 0.1 wt. % to 7 wt. %.
All the abovementioned active substances may optionally also be
used in the form of their pharmacologically acceptable salts
thereof.
The combined preparations are preferably formulations in which
tiotropium is present in solution. The other active substance may
be dissolved or suspended; this is generally determined by the
other active substance and the particular solvent used.
If the additional active substance is one which is vulnerable at
low pHs, it is preferably formulated as a suspension. The advantage
of a suspended form is that the pH can be made more acidic, which
is to the benefit of the stability of the dissolved tiotropium. The
preferred pH range of tiotropium bromide is between 2.0 and 4.5,
preferably 2.5 and 3.5, most preferably between 2.7 and 3.2.
In the case of steroids, these are preferably used in suspended
form, especially fluticasone. This is particularly true if the
solvent used is only water without ethanol. If ethanol is added,
the steroid may also be formulated as a solution. However, it has
been found that budesonide, for example, is also sufficiently
stable at a pH of 3.5 if it is dissolved in a mixture of water and
ethanol.
With regard to the use of the formulations according to the
invention in the inhaler described within the scope of the present
invention, it may be advantageous if all the ingredients of the
formulation are present in solution.
As well as ethanol, other cosolvents and/or other adjuvants may be
added to the formulation according to the invention.
Other preferred cosolvents are those which contain hydroxyl groups
or other polar groups, for example, alcohols, especially isopropyl
alcohol, glycols--especially propylene glycol, polyethylene glycol,
polypropylene glycol, glycol ether, glycerol, polyoxyethylene
alcohols, and polyoxyethylene fatty acid esters.
By adjuvants and additives are meant, in this context, any
pharmacologically acceptable and therapeutically useful substance
which is not an active substance, but can be formulated together
with the active substance(s) in the pharmacologically suitable
solvent, in order to improve the qualities of the active substance
formulation. Preferably, these substances have no pharmacological
effects or no appreciable or at least no undesirable
pharmacological effects in the context of the desired therapy. The
adjuvants and additives include, for example, surfactants such as,
e.g., soya lecithin, oleic acid, sorbitan esters such as sorbitan
trioleate, polyvinylpyrrolidone, other stabilizers, complexing
agents, antioxidants and/or preservatives which prolong the shelf
life of the finished pharmaceutical formulation, flavorings,
vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium
chloride, for example.
Suitable surfactants or suspension-stabilizing agents include all
the pharmacologically acceptable substances which have a lipophilic
hydrocarbon group and one or more functional hydrophilic groups,
especially C.sub.5-20 -fatty alcohols, C.sub.5-20 -fatty acids,
C.sub.5-20 -fatty acid esters, lecithin, glycerides,
propyleneglycol esters, polyoxyethylenes, polysorbates, sorbitan
esters and/or carbohydrates. C.sub.5-20 -fatty acids,
propyleneglycol diesters and/or triglycerides and/or sorbitans of
the C.sub.5-20 -fatty acids are preferred, while oleic acid and
sorbitan mono-, di- or trioleates are particularly preferred.
Alternatively, toxicologically and pharmaceutically acceptable
polymers and/or block polymers may be used as suspension
stabilizing agents.
The quantity of surfactant may be up to 1:1 based on the proportion
by weight of the suspended active substances; amounts of 0.0001:1
to 0.5:1 are preferred while amounts of from 0.0001:1 to 0.25:1 are
especially preferred.
The preferred excipients include antioxidants such as ascorbic
acid, for example, provided that it has not already been used to
adjust the pH, vitamin A, vitamin E, tocopherols and similar
vitamins or provitamins occurring in the human body.
Preservatives can be added to protect the formulation from
contamination with pathogenic bacteria. Suitable preservatives are
those known from the prior art, particularly benzalkonium chloride
or benzoic acid or benzoates, such as sodium benzoate, in the
concentration known from the prior art.
Preferred formulations contain only benzalkonium chloride, an acid
for adjusting the pH and sodium edetate, in addition to the solvent
water and/or water/ethanol and the tiotropium salt.
In another preferred embodiment, sodium edetate is omitted. These
embodiments may optionally also contain sodium chloride.
As already mentioned a number of times, tiotropium bromide is
described in EP 418 716 A1 and crystalline tiotropium bromide
monohydrate may be obtained using a process which is described in
more detail below.
In order to prepare the crystalline monohydrate according to the
present invention, the tiotropium bromide obtained by the method
disclosed in EP 418 716 A1, for example, first has to be taken up
in water, heated, purified with activated charcoal and, after
removal of the activated charcoal, the tiotropium
bromide-monohydrate is slowly crystallized while cooling
slowly.
The following procedure is preferably followed:
In a reaction vessel of suitable dimensions, the solvent is mixed
with tiotropium bromide, which has been obtained by the method
disclosed in EP 418 716 A1, for example.
For each mole of tiotropium bromide put in, 0.4 to 1.5 kg,
preferably 0.6 to 1 kg, most preferably about 0.8 kg of water are
used as solvent.
The mixture obtained is heated with stirring, preferably to above
50.degree. C., most preferably to above 60.degree. C. The maximum
temperature which can be selected is determined by the boiling
point of the solvent used. Preferably, the mixture is heated to a
range from 80.degree. C. to 90.degree. C. Activated charcoal,
either dry or moistened with water, is added to this solution.
Preferably, 10 g to 50 g, more preferably 15 g to 35 g, most
preferably about 25 g of activated charcoal are put in per mol of
tiotropium bromide used. If desired the activated charcoal is
suspended in water before being added to the solution containing
tiotropium bromide. 70 g to 200 g, preferably 100 g to 160 g, more
preferably about 135 g of water are used, per mol of tiotropium
bromide put in, in order to suspend the activated charcoal. If the
activated charcoal is suspended in water beforehand, before being
added to the solution containing tiotropium bromide, it is
advisable to rinse again with the same amount of water. After the
activated charcoal has been added, stirring is continued at
constant temperature for between 5 minutes and 60 minutes,
preferably between 10 minutes and 30 minutes, more preferably for
about 15 minutes and the mixture obtained is filtered to remove the
activated charcoal. The filter is then rinsed with water. 140 g to
400 g, preferably 200 g to 320 g, most preferably about 270 g of
water are used for this, per mol of tiotropium bromide used. The
filtrate is then slowly cooled, preferably to a temperature of
20.degree. C. to 25.degree. C. The cooling preferably takes place
at a cooling rate of 1 to 10.degree. C. every 10 to 30 minutes,
preferably 2.degree. C. to 8.degree. C. every 10 to 30 minutes,
more preferably 3.degree. C. to 5.degree. C. every 10 to 20
minutes, most preferably 3.degree. C. to 5.degree. C. about every
20 minutes. If desired the cooling to 20.degree. C. to 25.degree.
C. may be followed by further cooling to below 20.degree. C., more
preferably to 10.degree. C. to 15.degree. C. After cooling is
complete, stirring is continued for between 20 minutes and 3 hours,
preferably between 40 minutes and 2 hours, more preferably for
about one hour to complete the crystallization. The crystals
obtained are then isolated by filtering or suction filtering to
remove the solvent. If it should prove necessary to subject the
crystals obtained to a further washing step, it is advisable to use
water or acetone as the washing solvent. 0.1 L to 1.0 L, preferably
0.2 L to 0.5 L, more preferably about 0.3 L of solvent may be used
per mol of tiotropium bromide put in, in order to wash the
tiotropium bromide monohydrate crystals obtained. If necessary the
washing step may be repeated. The product obtained is dried in
vacuo or using circulating heated air until a water content of 2.5%
to 4.0% is obtained.
According to one aspect the present invention therefore also
relates to formulations of solutions of the type described above
using crystalline tiotropium bromide monohydrate which may be
obtained by the procedure described above.
The pharmaceutical formulations containing tiotropium salts
according to the invention are preferably used in an inhaler of the
kind described hereinbefore in order to produce the propellant-free
aerosols according to the invention. At this point we should once
again expressly mention the patent documents described
hereinbefore, to which reference is hereby made.
As described at the beginning, a further developed embodiment of
the preferred inhaler is disclosed in WO 97/12687 and FIG. 6
thereof. This nebulizer (RESPIMAT.RTM.) can advantageously be used
to produce the inhalable aerosols according to the invention
containing a tiotropium salt as active substance. Because of its
cylindrical shape and handy size of less than 9 cm to 15 cm long
and 2 cm to 4 cm wide, the device can be carried anywhere by the
patient. The nebulizer sprays a defined volume of the
pharmaceutical formulation out through small nozzles at high
pressures, so as to produce inhalable aerosols.
The preferred atomizer essentially consists of an upper housing
part, a pump housing, a nozzle, a locking clamp, a spring housing,
a spring and a storage container, characterized by
a pump housing fixed in the upper housing part and carrying at one
end a nozzle body with the nozzle or nozzle arrangement,
a hollow piston with valve body,
a power take-off flange in which the hollow body is fixed and which
is located in the upper housing part,
a locking clamping mechanism located in the upper housing part,
a spring housing with the spring located therein, which is
rotatably mounted on the upper housing part by means of a rotary
bearing,
a lower housing part which is fitted onto the spring housing in the
axial direction.
The hollow piston with valve body corresponds to a device disclosed
in WO 97/12687. It projects partially into the cylinder of the pump
housing and is disposed to be axially movable in the cylinder.
Reference is made particularly to FIGS. 1 to 4, especially FIG. 3,
and the associated parts of the description. At the moment of
release of the spring the hollow piston with valve body exerts, at
its high pressure end, a pressure of 5 MPa to 60 MPa (about 50 to
600 bar), preferably 10 MPa to 60 MPa (about 100 to 600 bar) on the
fluid, the measured amount of active substance solution. Volumes of
10 to 50 microliters are preferred, volumes of 10 to 20 microliters
are more preferable, whilst a volume of 15 microliters per
actuation is particularly preferred.
The valve body is preferably mounted at the end of the hollow
piston which faces the nozzle body.
The nozzle in the nozzle body is preferably microstructured, i.e.,
produced by micro-engineering. Microstructured nozzle bodies are
disclosed for example in WO 94/07607; reference is hereby made to
the contents of this specification, especially FIG. 1 and the
associated description, and which is incorporated herein by
reference in its entirety.
The nozzle body consists for example of two sheets of glass and/or
silicon securely fixed together, at least one of which has one or
more microstructured channels which connect the nozzle inlet end to
the nozzle outlet end. At the nozzle outlet end there is at least
one round or non-round opening 2 microns to 10 microns deep and 5
microns to 15 microns wide, the depth preferably being 4.5 microns
to 6.5 microns and the length being 7 microns to 9 microns.
If there are a plurality of nozzle openings, preferably two, the
directions of spraying of the nozzles in the nozzle body may run
parallel to each other or may be inclined relative to one another
in the direction of the nozzle opening. In the case of a nozzle
body having at least two nozzle openings at the outlet end, the
directions of spraying may be inclined relative to one another at
an angle of 20.degree. to 160.degree., preferably at an angle of
60.degree. to 150.degree., most preferably 80.degree. to
100.degree..
The nozzle openings are preferably arranged at a spacing of 10
microns to 200 microns, more preferably at a spacing of 10 microns
to 100 microns, still more preferably 30 microns to 70 microns. A
spacing of 50 microns is most preferred.
The directions of spraying therefore meet in the region of the
nozzle openings.
As already mentioned, the liquid pharmaceutical preparation hits
the nozzle body at an entry pressure of up to 600 bar, preferably
200 bar to 300 bar and is atomized through the nozzle openings into
an inhalable aerosol. The preferred particle sizes of the aerosol
are up to 20 microns, preferably 3 microns to 10 microns.
The locking clamping mechanism contains a spring, preferably a
cylindrical helical compression spring as a store for the
mechanical energy. The spring acts on the power take-off flange as
a spring member the movement of which is determined by the position
of a locking member. The travel of the power take-off flange is
precisely limited by an upper stop and a lower stop. The spring is
preferably tensioned via a stepping-up gear, e.g., a helical
sliding gear, by an external torque which is generated when the
upper housing part is turned relative to the spring housing in the
lower housing part. In this case, the upper housing part and the
power take-off flange contain a single- or multi-speed spline
gear.
The locking member with the engaging locking surfaces is arranged
in an annular configuration around the power take-off flange. It
consists for example of a ring of plastics or metal which is
inherently radially elastically deformable. The ring is arranged in
a plane perpendicular to the axis of the atomizer. After the
locking of the spring, the locking surfaces of the locking member
slide into the path of the power take-off flange and prevent the
spring from being released. The locking member is actuated by means
of a button. The actuating button is connected or coupled to the
locking member. In order to actuate the locking clamping mechanism
the actuating button is moved parallel to the annular plane,
preferably into the atomizer, and the deformable ring is thereby
deformed in the annular plane. Details of the construction of the
locking clamping mechanism are described in WO 97/20590.
The lower housing part is pushed axially over the spring housing
and covers the bearing, the drive for the spindle and the storage
container for the fluid.
When the atomizer is operated, the upper part of the housing is
rotated relative to the lower part, the lower part taking the
spring housing with it. The spring meanwhile is compressed and
biased by means of the helical sliding gear, and the clamping
mechanism engages automatically. The angle of rotation is
preferably a whole-number fraction of 360.degree., e.g.,
180.degree.. At the same time as the spring is tensioned, the power
take-off component in the upper housing part is moved along by a
given amount, the hollow piston is pulled back inside the cylinder
in the pump housing, as a result of which some of the fluid from
the storage container is sucked into the high pressure chamber in
front of the nozzle.
If desired, a plurality of replaceable storage containers
containing the fluid to be atomized can be inserted in the atomizer
one after another and then used. The storage container contains the
aqueous aerosol preparation according to the invention.
The atomizing process is initiated by gently pressing the actuating
button. The clamping mechanism then opens the way for the power
take-off component. The biased spring pushes the piston into the
cylinder in the pump housing. The fluid emerges from the nozzle of
the atomizer in the form of a spray.
Further details of the construction are disclosed in PCT
applications WO 97/12687 and WO 97/20590, to which reference is
hereby made and each of which is incorporated herein by reference
in their entireties.
The components of the atomizer (nebulizer) are made of a material
suitable for their function. The housing of the atomizer and, if
the function allows, other parts as well are preferably made of
plastics, e.g., by injection moulding. For medical applications,
physiologically acceptable materials are used.
FIGS. 1a/b, which are identical to FIGS. 6a/b of WO 97/12687, show
the RESPIMAT.RTM. nebulizer with which the aqueous aerosol
preparations according to the invention can advantageously be
inhaled.
FIG. 1a shows a longitudinal section through the atomizer with the
spring under tension, and FIG. 1b shows a longitudinal section
through the atomizer with the spring released.
The upper housing part (51) contains the pump housing (52), on the
end of which is mounted the holder (53) for the atomizer nozzle. In
the holder is the nozzle body (54) and a filter (55). The hollow
piston (57) fixed in the power take-off flange (56) of the locking
clamping mechanism projects partly into the cylinder of the pump
housing. At its end the hollow piston carries the valve body (58).
The hollow piston is sealed off by the gasket (59). Inside the
upper housing part is the stop (60) on which the power take-off
flange rests when the spring is relaxed. Located on the power
take-off flange is the stop (61) on which the power take-off flange
rests when the spring is under tension. After the tensioning of the
spring, the locking member (62) slides between the stop (61) and a
support (63) in the upper housing part. The actuating button (64)
is connected to the locking member. The upper housing part ends in
the mouthpiece (65) and is closed off by the removable protective
cap (66).
The spring housing (67) with compression spring (68) is rotatably
mounted on the upper housing part by means of the snap-fit lugs
(69) and rotary bearings. The lower housing part (70) is pushed
over the spring housing. Inside the spring housing is the
replaceable storage container (71) for the fluid (72) which is to
be atomized. The storage container is closed off by the stopper
(73), through which the hollow piston projects into the storage
container and dips its end into the fluid (supply of active
substance solution).
The spindle (74) for the mechanical counter is mounted on the
outside of the spring housing. The drive pinion (75) is located at
the end of the spindle facing the upper housing part. On the
spindle is the slider (76).
The nebulizer described above is suitable for nebulizing the
aerosol preparations according to the invention to form an aerosol
suitable for inhalation.
If the formulation according to the invention is nebulized using
the method described above (RESPIMAT.RTM.), the mass expelled, in
at least 97%, preferably at least 98% of all the actuations of the
inhaler (puffs), should correspond to a defined quantity with a
range of tolerance of not more than 25%, preferably 20% of this
quantity. Preferably, between 5 mg and 30 mg, more preferably
between 5 mg and 20 mg of formulation are delivered as a defined
mass per puff.
The proportion of the mass delivered which is outside a tolerance
limit of not more than 25% in relation to the desired mass should
be less than 1.5%, preferably less than 1.2%.
However, the formulation according to the invention can also be
nebulized using inhalers other than those described above, for
example jet-stream inhalers.
EXAMPLES
I. Example of the Synthesis of Tiotropium Bromide Monohydrate
15.0 kg of tiotropium bromide are added to 25.7 kg of water in a
suitable reaction vessel. The mixture is heated to 80.degree. C. to
90.degree. C. and stirred at constant temperature until a clear
solution is formed. Activated charcoal (0.8 kg), moistened with
water, is suspended in 4.4 kg of water, this mixture is added to
the solution containing tiotropium bromide and rinsed with 4.3 kg
of water. The mixture thus obtained is stirred for at least 15
minutes at 80.degree. C. to 90.degree. C. and then filtered through
a heated filter into an apparatus which has been preheated to an
outer temperature of 70.degree. C. The filter is rinsed with 8.6 kg
of water. The contents of the apparatus are cooled to a temperature
of 20.degree. C. to 25.degree. C. at a rate of 3.degree. C. to
5.degree. C. every 20 minutes. Using cold water, the apparatus is
cooled further to 10.degree. C. to 15.degree. C. and
crystallization is completed by stirring for at least another hour.
The crystals are isolated using a suction filter drier, the crystal
slurry isolated is washed with 9 L of cold water (10.degree. C. to
15.degree. C.) and cold acetone (10.degree. C. to 15.degree. C.).
The crystals obtained are dried at 25.degree. C. for 2 hours in a
nitrogen current. Yield: 13.4 kg of tiotropium bromide monohydrate
(86% of theory).
II. Examples of Formulations
TABLE I Pharmaceutical Formulations 100 g of Pharmaceutical
Preparation Contains the Following Amounts Tiotropium Tiotropium
Bromide Bromide Benzal- pH, Exam- (Based on Monohydrate konium
Sodium Adjusted ple Tiotropium) (Based on Chloride Edetate with HCl
No. (g) Tiotropium) (g) (mg) (mg) (1 N) 1 0.099 -- 10 25 3.0 2
0.006 -- 10 25 3.0 3 0.099 -- 10 10 3.0 4 0.006 -- 10 10 3.0 5 --
0.099 10 25 3.0 6 -- 0.006 10 25 3.0 7 -- 0.099 10 10 3.0 8 --
0.006 10 10 3.0 Note: The remainder of the pharmaceutical
formulation is water or water/ethanol and one of the
above-mentioned active substances in an amount known from the prior
art.
Examples 9 to 12.
Budesonide
Each of Examples 1 to 8 may additionally contain:
Example 9a: budesonide: 0.3 g, pH, adjusted with HCl:3.0, solvent
water only, no ethanol;
Example 9b: budesonide: 0.3 g, pH, adjusted with HCl:3,5;
Example 9c: budesonide: 0.3 g, pH, adjusted with HCl:4.0;
Example 10: analogous to Example 9a to 9c with budesonide: 0.6
g,
Example 11: analogous to Example 9a to 9c with budesonide: 1.3
g,
Example 12: analogous to Example 9a to 9c with budesonide: 2.0
g.
In Examples 9 to 12 the steroid is present in the formulation in
suspension. Sorbitan trioleate may be used as a surfactant.
Examples 13 to 15
Analogous to Examples 9 to 12. Benzalkonium chloride is exchanged
for sodium benzoate.
Examples 16 to 19
Analogous to Examples 9 to 12. Instead of hydrochloric acid, citric
acid is exclusively used to adjust the pH.
Examples 20 to 30
The ingredients and amounts are analogous to Examples 9 to 19.
Instead of water, a mixture of water (10 vol. %) and ethanol (90
vol. %) is used. Budesonide is present in solution.
Example 31
Epinastine: 0.2 g;
EDTA: 25 mg;
Tiotropium bromide monohydrate: 29 mg;
0.1 N hydrochloric acid to adjust the pH to 3.0; and
water to 100 ml.
Other Examples
Analogously to Examples 9 to 30 described above, the same amount of
flunisolide, beclomethasone dipropionate, or fluticasone is used
instead of budesonide. In the case of fluticasone, lecithin is
preferably added instead of sorbitan trioleate in the case of the
suspension formulation. The steroids are formulation as a
suspension if the solvent used is water on its own. In the case of
a mixture of water and ethanol, the steroid may be in solution.
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